If the goal of using unsealed sources of radiation therapy in the treatment of cancer is to be realized, the problem of locating internal emitters with a short range of action in the sensitive targets of the cell must be solved. Only two types of radioactivity satisfy these requirements: electron capture with subsequent Auger cascade (e.g., 125I) and alpha decay (e.g., 211 At). Using new carriers, exploitation of physical and pharmacological manipulations as well as the biology of individual tumors can help produce the distributions and therapeutic activities desired. This proposal addresses itself to the development of such strategies based upon physical, chemical and biological considerations and is aimed at answering some general quantitative questions about the potential use of Auger and alpha emitting radionuclides for tumor therapy. It has been shown in this laboratory and others that 125I is extremely cytotoxic when associated with DNA as a base analogue, an intercalating agent or a specifically translocated steroid sex hormone. 211 At is markedly radiotoxic in cultured mammalian cells and in colloidal form for the therapy of experimental malignant ascites. We will synthesize selected carrier-free 125I-labeled estrogens/ antiestrogens, establish receptor binding assays for cytoplasmic and nuclear fractions, determine the binding of these iodinated compounds relative to 17-beta-estradiol and measure both cytotoxicity and chromosomal aberrations as a function of clonogenic survival in cultured mammalian cell lines with characterized receptors. We also propose to test the in vitro cytotoxicity of carrier-free 125I-labeled melanin precursors in various pigmented and non-pigmented melanoma cell lines. Specific cellular accumulation can be investigated and cytotoxicity of these precursors measured. 211 At-labeled melanin precursors will be synthesized using those precursors that showed selective uptake when labeled with 125I. These 211At-precursors will be tested both in vivo and in vitro and their therapeutic efficacy evaluated.